Rocilinostat (ACY-1215)

Rocilinostat (ACY-1215) is a selective inhibitor of HDAC6 with IC50 of 5 nM [1].
HDAC6 (histone deacetylase 6) is an enzyme which encoded by the HDAC6 gene and plays an important role in translational regulation, cell cycle progression and developmental events. It has been revealed that over-expression of HDAC6 is correlated with tumorigenesis and cell survival and HDAC6 also involves in cancer cells metastasis [2] [3].
Rocilinostat (ACY-1215) is a selective HDAC6 inhibitor. When tested with human MM cell lines (MM.1S), treatment with ACY-1215 in increasing dose for 6 hours increased acetylated α-tubulin at a concentration of 0.62μM via inhibiting HDAC6 [1]. In multiple myeloma cells, used ACY-125 as an adjuvant with carfilzomib triggered synergistic anti-MM effects, even in bortezomib-resistant cells which resulted in enhance cells apoptosis [2].
In mouse model with xenografted human MM cells, administration of ACY-125 only or with bortezomib could markedly delay tumor growth and the combination showed best efficacy [1].
It is also reported that ACY-1215 has minimal activity against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2 (IC50 > 1μM), and has slight activity against HDAC8 (IC50 = 0.1μM) [1]. When tested with mouse xenografted MM cells, combination carfilzomib with ACY-1215 showed a decreased effect on tumor volume and cells apoptosis [2].
References:
[1].    Santo, L., et al., Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood, 2012. 119(11): p. 2579-89.
[2].    Mishima, Y., et al., Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol, 2015.
[3].    Haakenson, J., et al., HDAC6-Dependent Functions in Tumor Cells: Crossroad with the MAPK Pathways. Crit Rev Oncog, 2015. 20(1-2): p. 65-81.

Sensitive method for the determination of rocilinostat in small volume mouse plasma by LC-MS/MS and its application to a pharmacokinetic study in mice.[Pubmed:26633099]

Biomed Chromatogr. 2016 Jul;30(7):1138-1144.

A highly sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of rocilinostat in small volume mouse plasma (20 muL) using vorinostat as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a protein precipitation procedure with acetonitrile. Chromatography was achieved on Prodigy ODS-2 column using a binary gradient using mobile phase A (0.2% formic acid in water) and B (acetonitrile) at a flow rate of 0.38 mL/min. The total chromatographic run time was 4.1 min and the elution of rocilinostat and IS occurred at ~3.2 and 2.9 min, respectively. A linear response function was established in the concentration range of 0.28-1193 ng/mL in mouse plasma. The intra- and inter-day accuracy and precisions were in the ranges of 3.12-8.93 and 6.41-11.6%, respectively. This novel method has been applied to a pharmacokinetic study in mice. Copyright (c) 2016 John Wiley & Sons, Ltd.

Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial.[Pubmed:27646843]

Lancet Oncol. 2016 Nov;17(11):1569-1578.

BACKGROUND: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. METHODS: In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283. FINDINGS: Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response. INTERPRETATION: The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. FUNDING: Acetylon Pharmaceuticals.

Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling.[Pubmed:26150340]

Tumour Biol. 2015 Dec;36(12):9661-5.

Histone deacetylases (HDACs) play a role in the tumorigenesis of glioblastoma multiforme (GBM), whereas the underlying mechanism has not been elucidated. Here, we reported significantly higher HDAC6 levels in GBM from the patients. GBM cell growth was significantly inhibited by ACY-1215, a specific HDAC6 inhibitor. Further analyses show that HDAC6 may promote growth of GBM cells through inhibition of SMAD2 phosphorylation to downregulate p21. Thus, our data demonstrate a previously unrecognized regulation pathway in that HDAC6 increases GBM growth through attenuating transforming growth factor beta (TGFbeta) receptor signaling.

ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation.[Pubmed:28035401]

Oncol Rep. 2017 Feb;37(2):1270-1276.

BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia.[Pubmed:28712747]

Cell Chem Biol. 2017 Jul 20;24(7):892-906.e5.

Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor-mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.

Ricolinostat (ACY-1215) is a potent and selective HDAC6 inhibitor, with an IC50 of 5 nM. ACY-1215 also inhibits HDAC1, HDAC2, and HDAC3 with IC50s of 58, 48, and 51 nM, respectively.

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